The K99/R00 research and training plan will serve two purposes. The first is to provide substantial career development by: 1) expanding the investigator's area of expertise to include acetylcholine systems and their interaction with mesolimbic dopamine, 2) expanding the investigator's technical skill set to include rodent self-administration and fast scan cyclic voltammetry in freely moving animals, particularly in the detection of cue-evoked dopamine release, and 3) initiating a research program that will lead to research independence through professional development and collection of preliminary data for major research (R01) funding. The second corresponding purpose is to characterize a neurobiological mechanism for individual differences in the acquisition of drug self-administration behavior. Using a series of neurochemical and behavioral measures including microdialysis, HPLC, voltammetry in anesthetized and freely-moving animals, and self-administration, we will characterize individual differences in the magnitude of primary reward and conditioned cue-evoked dopamine release as well as corresponding propensity to self-administer cocaine and natural rewards. In addition, we will pharmacologically manipulate ventral tegmental area (VTA) and nucleus accumbens (NAc) nicotinic acetylcholine receptors (nAChRs) via acute and chronic administration of nicotine and subtype specific nAChR antagonists in order to demonstrate individual differences in their ability to modulate reward and cue-evoked dopamine transients. We propose that an underlying mechanism to explain individual differences in acquisition of drug self-administration behavior resides in the differental ability of VTA and NAc nAChRs to modulate dopamine release in the shell of the NAc in fast and slow acquiring animals.